PT86245B - PROCESS FOR THE PREPARATION OF 2-ARYLPROPIONIC ACIDS - Google Patents

Abstract

A stereospecific process for the preparation of a pharmaceutically active compound in at least 70% by weight S-configuration of the formula <CHEM> or a pharmaceutically acceptable salt or ester thereof, wherein R1 represents an optionally substituted aryl group such as a phenyl or naphthyl group, or R1 represents a heterocyclic ring system, which is optionally substituted, or R1 represents a heteroaromatic ring system optionally containing in addition to carbon atoms one or more atoms of nitrogen, sulphur or oxygen atoms, this ring system being optionally substituted, comprises subjecting a compound of the formula <CHEM> wherein R2 is an alkyl group containing at least 3 carbon atoms, to the action of a micro-organism or substances derived therefrom capable of stereoselective oxidation of compound (II) into compound (I), having at least 70% by weight S-configuration.

Description

DESCRIPTIVE MEMORY

The present invention relates to a stereospecific process for the preparation of 2-arylpropionic acids, preferably of a pharmaceutically active compound with at least 70% by weight in the S configuration,

Many biologically active compounds are synthesized in the form of a mixture of stereoisomers. Such mixtures are often used in pharmaceutical and agronomic applications. Usually the desired biological activity predominantly resides in only one of the stereochemical isomers so that when the mixture contains two or more stereoisomers the potency of the mixture is reduced. A major reason for the continued use of mixtures of stereoisomers is that the cost of separating the stereoisomers exceeds the potential advantage of a possible increase in activity. However, it is apparent that modern pharmacologists are becoming increasingly aware of other implications of administering mixtures in which one or more stereoisomers have to be viewed merely as impurities that may not have the desired therapeutic effect, but may even have other effects. unwanted physiological effects including toxicity.

More particularly, it is known that the in vitro anti-inflammatory activity of naproxen as well as ibuprofen resides in the S-enentiomer (optically active stereoisomer) which is up to 150 times as active as its antipode (S. Adams et al. J. Pharm. Pharmac., 28 (1976) 256 and AJ Hutt and J. Cal dwell, Clinicai Pharmacokinetics £ (1984) 371)

The selective preparation of inactive R enantiomers of ibuprofen is known by microbial oxidation of l-isobutyl-4 (1'-methyloctyl-benzene, an aromatic hydrocarbon that has a suitable non-functional aliphatic side chain, through T. Sugai and K. Mori (Agric. Biol, Chem., 48 (1984) 2501).

There is still a great need for an industrial scale process in an economically attractive way for the preparation of these S enantiomers. Thus one of the aims of the present invention is to provide such a process.

As a result of extensive research and experimentation, there is now surprisingly a stereoselective process for the preparation of 2-arylpropionic acids, preferably of a pharmaceutically active compound in which at least 7CP / o by weight in the .S configuration of the formula

CH.

/

- CH (l) \

COOH or a pharmaceutically acceptable salt or ester derived therefrom, in which R4 represents an optionally substituted aryl group such as a phenyl or naphthyl group, or R4 represents a heteroaromatic ring system containing in addition to the carbon atoms one or more atoms nitrogen, sulfur or oxygen, this ring system being optionally substituted, which comprises subjecting a compound of formula

R_ - CH (li) ¹ \ r ₂ in which R ^ is as defined above and Rg is an alkyl group containing at least 3 carbon atoms, due to the action of a microorganism or substances derived from it, capable of stereoselective oxidation from compound (li) to compound (l), predominantly in the S configuration, and if it is desired to convert the compound (i) into a pharmaceutically acceptable salt or ester derived therefrom.

By the term predominantly in the S configuration we mean that more than 50% by weight of the resulting compound (l) has S configuration and in practice, according to our invention, a microorganism or substances derived from it capable of stereoselective oxidation of the compound is used (li) in compound (l) with at least 7θ% by weight of S configuration, preferably at least 80% by weight and in particular with at least 90% by weight of S configuration.

The salt or ester of the pharmaceutically acceptable compound (1) is preferably the salt of an alkali metal or the salt of an alkaline earth metal. it is an alkyl group containing at least 3 carbon atoms, optionally substituted with, for example, pentane, heptane or nonnate. Preferably

The compound (i) is naproxen, ibuprofen, suprofen, fenoprofen, ketoprofen, benoxaprofen, carprofen, cycloprophene, pyrprofen, lisiprofen, flurbiprofen, fluprofen, clidanac, tertiprofen, hexaprofen, indoprofen, mexoprofen, 80pranopro acid , thiaprofenic acid or brofezil.

According to a preferred embodiment of the present invention, naproxen or ibuprofen is prepared predominantly in the S configuration and Rg is a linear alkyl containing 3-11 carbon atoms.

Compound (li) can be obtained using known methods or methods that are planable by a person skilled in the art. For example, 2- (6-methoxy-2-naphthyl) -alkanes are synthesized from 2-bromo-o-methoxynaphthalenes. The last compound is reacted with a 2-alkanone resulting in 2-hydroxy-2- (6-methoxy-2-naphthyl) -alkane. Subsequently, the product is converted to 2- (o-methoxy-2-naphthyl) -alken-2 and hydrogenated, resulting in 2- (6-methoxy-2-naphthyl) -alkane.

It is not possible to obtain only the compound (l) enriched in the S-isomer according to the process of the invention, the compound (li) enriched in the R-isomer is also a product of this process. The latter remains as long as the S-isomer is converted by a microorganism or substances derived therefrom.

Unlike oxidation from 2-arylpropane with a possible stereoselective oxidation with 100% conversion to 2-arylpropionic acids-S, oxidation of the compound (li) results in a maximum 50% conversion from a racemic mixture of compound ( li).

The microorganisms used in the process according to the invention are capable of not only stereoselectively oxidizing the compound (li) but also of oxidizing only in the first carbon position of Rg.

By the term microorganisms having the capacity for stereoselective oxidation we mean, for example, fungi, yeast-like fungi, yeasts and bacteria and include microorganisms belonging to the genus Exophiala, Rhinocladiella and Graphium.

Microorganisms capable of oxidizing compound (li) to compound (l) include Exophiala .jeanselmei (a strain of this species is registered as an example in CBS under registration number 537 * 76) »Exophiala mansonii (a strain of this species is registered in CBS under registration number 101.67) t Exophiala .jeanselmei var. heteromorpha (a strain of this species is registered in CBS under registration number 232.331, Rhinocladiella spinifera (a strain of this species is registered in CBS under registration number 269.28), Exophialla dermatitis (a strain of this species is registered in CBS under number registration number 207.35) and Exophialla alcalophila (a strain of this species is registered in CBS under registration number 520.82).

In a embodiment of the invention, microorganisms capable of stereoselective oxidation of compound (li) to compound (i) can be selected from a natural source by contacting the natural source with a 2- (R3) - alkane ( R ^ is defined as above) as a source of C in a suitable medium. Conveniently 2- (6-methoxy-2-naphthyl) -alkane is used for the selection of microorganisms having the ability to prepare naproxen, the alkane being advantageously pentane, heptane or nonane. A suitable medium is, for example, a PSlII salt medium enriched with a solution of vitamins and / or 0.01% yeast extract.

A number of microorganisms isolated from natural sources were selected, particularly from soil samples, according to the selection process above and when subjected to further tests as described below, they showed their capacity for stereoselective composition oxidation (n ) to compound (i).

- 5 Some of the microorganisms used for the invention can be isolated from soil samples using 2.5 g / 1 of 2- (6-methoxy-2-naphthyl) -heptane as a C source in PSIU salt medium enriched with a solution of vitamins and / or 0.01% yeast extract.

The composition of a PSIII salt medium contains: kh ₂ po _u (2.1 g / 1), (nh _u ) ₂ hpo ₄ (1.0 g / 1), (nh ₄ ) ₂ so ₄ (0.9 g / 1), KCl (o, 2 g / 1), CaSO ₄ . 2 HgO (0.005 g / 1), MgSO4. 7 Η ,, Ο (0.2 g / 1), (NH ₄ ) ₂ SO ₄ .FeSO ₄ . 6 Η _£ 0 (2.5 mg / 1), ZnSO4. 7 Η ,, Ο (θ, 5 mg / 1), MnCl ₂ . 4 Η _£ 0 (0.3 mg / 1), CuSO4. 5 Η ,, Ο (θ, 15 mg / 1), CoCl ₂ . 6 H ₂ O (0.15 mg / 1), H ^ BO ^ (0.05 mg / 1), NagMoO ^. 2 (0.055 mg / 1), Kl (0.1 mg / 1).

The pH was adjusted to 6.8. The medium was sterilized for 20 minutes at 120 ° C.

The composition of the vitamin solution contains: Biotin (0.002 mg / 1), Calcium pentotenate (θ, 4 mg / 1), Inosi tol (2.0 mg / 1), Nicotinic acid (0.4 mg / 1), Thiamine-HCl (o, 4 mg / 1), Pyridoxine-HCl (0.4 mg / 1), p-aminobenzoic acid (0.2 mg / 1), Rlboflavin (0.2 mg / 1), Folic acid ( 0.01 mg / 1).

The pH was adjusted to 7.0 and the medium was sterilized using a membrane filter.

The newly discovered microorganisms were purified with solidified agar medium.

Examples of these cultures were recorded on CBS.

Microorganisms for the oxidation of compound (li) to compound (l), obtained by the aforementioned isolation and selection method include Graphium fructicola (a strain of this species is registered with CBS under registration number 256.86 on May 15, 1986) , Exophiala mansonii (a strain of this species is registered with CBS under the number of

to 257 * 86 on May 15, 1986), Exophiala masonii (a strain of this species is registered in CBS under registration number 259.86 on May 15, 1986), Exophiala jeanselmei var, jeanselmei (a strain of this species is registered on CBS under registration number 258.86 to 15 of M _to i ₀ of 19θό) and variants or mutants derived therefrom. These newly registered microorganisms form yet another embodiment of the present invention.

This definition also covers microorganisms that have obtained the capacity for stereoselective oxidation through the introduction of foreign genetic material. This can be done by transferring the cloned gene encoding a polypeptide responsible for stereoselective oxidation, for example, an enzyme, from a suitable microorganism to another microorganism, particularly Escherichia coli. Other microorganisms may belong to the genus Pseudomonas, Mycobaçterium, Streptomyces, Saccharomyces, Kluyveromyces, Bacillus, Nocardia, Rhodococus, Escherichia and Gorynebacterium. Cloned genes can be selected for their ability to encode an enzyme capable of oxidizing the stereosis of the compound (li).

Alternatively, they can be selected by cross-hybridization with an already selected gene that encodes an enzyme for stereoselective epoxidation.

The microorganisms can advantageously be immobilized, for example, on a gel polymer. This can be done with live cells, dead cells and / or resting cells, or with suitable enzymes and derivatives thereof, which can be purified to a certain extent if a higher specific activity is required. For this reason the term microorganisms or substances derived from them means dead, living or resting microorganisms and extracts derived from them such as enzymes or metabolites, optionally concentrated and / or purified. For example, enzymes can optionally be used in combination with, for example, artificial or natural cofactors.

raises. Preferably, non-fermentative cells should be used for the oxidation of the compound (li). It has been found that enzymes from living cell strains or dead cells can produce the S isomer under suitable conditions. Microorganisms or substances derived from them may be used several times. Microorganisms can remain active even without a cosubstrate (for example glucose). The S-isomer enrichment of compound (i) can take place in suitable buffers as well as in physiological ones.

In the practice of a preferred embodiment of the process of the present invention, a microorganism having the ability to convert the compound (li) into compound (l) with at least 7θ / ³ weight can be grown for about 0.5 to 10 days. configuration S. After that, the cells can be suspended in a liquid nutrient medium, preferably a minimal liquid nutrient medium, and the compound (l1) is subjected to the action of the cells. Alternatively, the cells can be killed by suspending, for example, in a lysis medium and subjecting the 4-allyloxyphenyl acetate to the action of substances derived from the cells. After this culture for about 1 to 10 days, the cells can be isolated from the culture medium before being suspended in the liquid nutrient medium or suspended in a lysis medium. To develop the microorganisms used for the selective oxidation of the compound (li) ordinary culture media containing an assimilable carbon source (for example glucose, lactate, sucrose, etc.), a nitrogen source (for example sulfate) ammonium, ammonium nitrate, ammonium chloride, etc.) with an agent for a source of organic nutrient (eg yeast extract, peptone, malt extract, meat extract, etc.) and a source of inorganic nutrient (eg phosphate, magnesium, potassium, zinc, iron and other metals in trace amounts). A preferred culture medium is a Gzapeck-Dox medium, a BHI medium or a YEPD medium optionally enriched with one or more ingredients,

A temperature from 0 to

45 ° C and a pH of 3.5 to 8 during the growth of microorganisms. Preferably, microorganisms grow at a temperature of 20 to 37 ° C and a pH of 4 to 7 ·

The aerobic conditions necessary during the development of the microorganisms can be provided by any of the well-known processes, as long as the oxygen supply is sufficient for the metabolic needs of the microorganisms. This is achieved very conveniently by supplying oxygen, preferably in the form of air. During the conversion of compound (l1) to compound (l) the microorganisms can be in a growth phase using one of the culture media mentioned above. Microorganisms can be supplemented with a cosubstrate.

During the conversion of compound (li) to compound (i) the microorganisms can be maintained in a growth stage or in a substantially non-growth stage using a minimal culture medium. As a minimum culture medium, ordinary culture medium containing an assimilable carbon source when needed (eg glucose, lactate, sucrose, etc.), a nitrogen source when needed (eg ammonium sulphate, ammonium nitrate, ammonium chloride, etc.) with an agent for an organic nutrient source when needed (eg yeast extract, malt extract, peptone, meat extract, etc.) and an inorganic nutrient source when required (eg phosphate, magnesium, potassium, zinc, iron and other metals in trace amounts). Organisms can be maintained at the non-growth stage for example by excluding the assimilable carbon source or by excluding the nitrogen source. During this stage, a temperature of 0 to ^ 5 ° C and a pH of 3.5 to 8 are normally maintained. Preferably the organisms are kept at a temperature of 20 to 37 ° C and a pH of 4 to 7 · The aerobic conditions required during this stage can be provided according to the procedures mentioned above, as long as the oxygen supply is sufficient to go

against the metabolic needs of microorganisms but also to convert the compound (li) into compound (l). The compound (1) produced by the microorganisms can be recovered and purified as mentioned above by any of the methods known per se for such products. Advantageously, the substrate to be transformed (compound (Ti)) was added to the growing or already developed culture and incubated after 5 hours to 10 days.

The following examples illustrate the invention without restricting its scope.

Example I

The conversion of 2- (o-methoxy-2-naphthyl) -heptane to S-2 ~ (6-methoxy-2-naphthyl) -propanoic acid using fungi

Fungal organisms on agar declining or deep-frozen were kept in 50% glycerol. For the experiment, they were inoculated directly into the test medium or pre-cultured in YEPD medium at 30 ° C. In the case of a pre-culture, the organisms were grown until complete growth was established after which 2-10% of the culture was inoculated in fresh test medium.

YEPD medium contains: Bactopeptone 20 g / 1, Yeast extract 10 g / 1 and glucose 20 g / 1. The pH was adjusted to 7.0. The medium was sterilized for 30 minutes at 110 ° C.

For each assay, 100 ml of YEPD medium was used preserving in a 500 ml bottle. All tests were performed at least in duplicate. For yeast-like fungi, septum flasks were always used. The filamentous fungi developed in normal flasks and were transferred to flasks with septum at the time of the addition of 2- (o-methoxy-2-naphthyl) -heptane.

The microorganisms were allowed to develop for U8 hours. Then, 4θ 71I of 2- (6-methoxy-2-naphthyl) -heptane was added to the cultures. The cultures were incubated again for 1 or 3 days at 3 ° C and then extracted with 40 ml of dichloromethane after addition at pH 2.0 with a small amount of ammonium sulphate.

and the addition

The extracts were analyzed by HPLC using a silica gel chrompack column (CP-Sper-Si) eluted with ethyl acetate / isooctane (1: 7) acidified with 3.5 ml formic acid per liter.

Extracts containing compounds with the same retention time as naproxen were used for a derivatization process. The naproxen present was converted to a naphthalene-derived methylamide in order to determine its enantiomeric purity.

Deratization and enantiomer separation process

The sample was evaporated from 8 to 12 ml of dichloromethane extract under a constant stream of N ₂ at 0 ° C. The dry sample was taken in 2 ml of dichloromethane and allowed to react for 10 minutes at 60 ° C with 200 µl of a solution of 2-bromo-1-methylpyridine iodide dissolved in dimethylformamide (50 mg / ml) and 20 ^ 11 of a solution of 1-naphthalenomethylamide dissolved in C ^ Cl ^ (100 mg / ml).

The reaction mixture was dried under 0 ° C. The residue was then dissolved first in 2 ml of isooctane / CH ₂ C1 ₂ (2: 1 v / v) and extracted after adding 2 ml of 1N HCl. The organic layer was then analyzed on HPLC using a chiral DNBPGr column eluted with isooctane / chloroform / methanol (90/7/3 v / v)

The results are shown in Table I.

Table I

Mi c ro o rgani s mo Time point- Naproxen * formed (mg / 1) % R cation ral after attaché substra (days) Exophiala mansonii 1 4.5 74 26 (CBS 257.86) 3 5.7 78 22 Exophiala mansonii (CBS 259.86) 3 9.5 73 27 Exophiala jeanselmei 1 8.4 ** ^83x 17 ^S3f var. jeanselmei (CBS 258.86) 3 18 99 1 Graphium fructicola 3 6.8 86 14 (CBS 256.86) Exophiala jeanselmei 1 10 90 10 (CBS 537.76) 3 16 98 2

Exophiala mansonii 1 11 86 14 (CBS 101.67) 3 17 82 18

Table I (continued)

Mi c ro o rgani s mo

Time point after adding the substrate

Naproxen formed (mg / 1)

(days)

Exophiala jeanselmei var. heteromorpha (CBS 232.33)

2.0 90 10

Rhinocladiella spinifera (CBS 269.28)

0.8 100 ^X The indicated value is the amount of naproxen found after derivatization. Each quantity represents the average of two values obtained. Only the data marked with xx was obtained from a single experiment.

Example II

The conversion of 2- (6-methoxy-2-naphthyl) -pentane to 3-2- (6-methoxy-2-naphthyl) -propanoic acid (S-naproxen) using fungi

All tests were performed as described in Example I, but instead of adding 2- (6-methoxy-2-naphthyl) -heptane, 4th p.1 of 2- (6-methoxy-2-naphth) was added useful) -tane to cultures.

The results are shown in table II

Table II

X Microorganisms Naproxen% S time point % R after substrate addition (days) of formed (mg / 1) Exophiala mansonii 3 (CBS 257.86) 11 75 25 Exophiala jeanselmei 3 var. jeanselmei (CBS 258.86) 4.1 100 - Graphium fructicola 3 (CBS 256.86) 6.2 85 15 Exophiala dermatitis 3 (CBS 207.35) 6.1 71 29 Exophiala jeanselmei 3 (CBS 537.76) 21 98 2 Exophiala alcalophila 3 (CBS 520.82) 3.1 79 21 Rhinocladiella spinifera 3 (CBS 269.28) 0.6 100 - ~ The indicated value is the quantity in naproxen found after

derivatization. Each quantity represents the average of two values obtained.

Example III

Conversion of 2- (6-methoxy-2-naphthyl) -nanane to S-2- (6-methoxy-2-naphthyl) -propanoic acid (o-naproxen) using fungi

All tests were performed as described in Example I but instead of adding 2- (Î ± -methoxy-2-naphthyl) heptane, 4µl of 2- (6-methoxy-2-naphth) was added. il) -nano to cultures.

The results are shown in table III

Table III

Mi c ro o rgani s mo Time point after adding the substrate (days) Naproxen *% S formed (mg / 1) % R Exophiala mansonii (CBS 257.86) 3 27.6 80 20 Exophiala mansonii (CBS 259.86) Exophiala jeanselmei 3 22.5 70 30 var. jeanselmei (CBS 258.86) 3 10.8 100 “· Graphium fructicola (CBS 256.86) 3 9.3 73 27 Exophiala jeanselmei (CBS 537.76) 3 25 ^SX Exophiala alcalophila (CBS 520.82) 3 O ^86x Exophiala mansonii (CBS 101.67) 3 2.5 81 19 Rhinocladiella spinifera 3 1.0 100 -

(CBS 269.28) * The indicated value is the amount of naproxen found after derivatization. Each quantity represents the average of two values obtained.

Only the data marked with xx was obtained from a single experiment

Example IV:

Isolation and identification of S-2- (o-methoxy-2-naphthyl) -propanoic acid (S-naproxen) formed by the fungus Exophida Jeansel mei var. jeanselmei (CBS 258.86)

A total of 500 ml of Exophida .jeanselmei var. jeanselmei (CBS 258.86), developed in YEPD medium, in which 2- (6-methoxy-2-naphthyl) -he ptane was transformed into naproxen as described in Example I, for a process of isolation and identification of the formed naproxen.

The culture broth was made acidic and extracted several times with CH2 lg. After CH2 Clg evaporation, 0.16 g of product remained. The residue was dissolved in 10 ml of diethyl ether and extracted with 3x5 ml of 1M NaHCO3. The aqueous phase was acidified and re-extracted with 3x5 ml of dimethyl ether. After washing the organic phase with NaCl at 30%, the extract was dried over Na2 SO4 and after evaporation of diethyl ether, 20 mg of crude residue were obtained. The residue was analyzed with ^ HmR and naproxen being one of the compounds present by the following characteristic signs:

Ô 1.59 ppm (doublet, 3H, coupling constant 7 Hz) <3 3.91 ppm (singlet, 3H OCH ^) ^ 7.12 ppm (multiplet, 2Η naphthyl)

7, ^ 2 ppm (double doublet, 1H naphthyl) ^ 7.70 ppm (multiplet, 3H naphthyl)

Claims (1)

R Ε IV I N HINTS - 1 * Stereospecific process for the preparation of a pharmaceutically active compound with at least 70% by weight of the S configuration of the formula CH „/ ³ R. - CH (l) ¹ \ COOH or a pharmaceutically acceptable salt or ester derived therefrom, in which R R represents an optionally substituted aryl group such as a phenyl group or a naphthyl group, or represents a heterocyclic ring system, which is optionally substituted, or R ^ represents a heteroaromatic ring system optionally containing in addition to the carbon atoms one or more nitrogen, sulfur or oxygen atoms, this ring system being optionally substituted, characterized by subjecting a compound of formula CH „/ ³ R, - CH (li) ¹ \ ^R 2 in which R ^ is as defined above and Rg is an alkyl group containing at least 3 carbon atoms, due to the action of a microorganism or substances derived from it capable of stereoselective oxidation of the compound (li) the compound (l) with at least 7θ%> by weight of the S configuration and if it is desired to convert the compound (i) into a pharmaceutically acceptable salt or ester derived therefrom. - 2 * 17 Process according to claim 1, characterized in that the compound (i) is naproxen, ibuprofen, oicloprofen, suprofen, carprofen, ketoprofen, benoxaprofen, fenoprofen, pyrprofen, lisiprofen, flurbi pro haeno, fluprofen no, clidinac, tertiprofen, hexaprofen, indoprofen, mexoprofene, pranoprofen, R 803, protizinic acid, thiaproic acid or brofezil. Process according to claim 2, characterized in that the compound (i) is naproxen or ibuprofen. Process according to any one of the preceding claims, characterized in that said microorganisms of substances derived from them are capable of converting a compound (li) into compound (l) with at least 90% by weight of S configuration. - _ Process according to any of the preceding claims, characterized in that said microorganisms or substances derived from them are isolated and selected from natural sources using 2- (R () - alkane as the source of C in a suitable medium. - 6® 18 Process according to claim 5, characterized in that it is a 6-methoxy-2-naphthyl group and the alkane is pentane, heptane or nonane. Process according to any of the preceding claims, characterized in that said microorganism is a fungus, a yeast, a yeast-like fungus or a bacterium. 8. A process according to claim 7, characterized in that said microorganism belongs to the genus Graphium, - 9 * - Process according to claim 7, characterized in that said microorganism belongs to the genus Exophíala. 10. The process of claim 7 wherein said microorganism belongs to the genus Rhinocladiella. - 11 * 19 - Process according to any of the preceding claims, characterized in that said microorganism or substances derived therefrom are immobilized. Process for the preparation of a pharmaceutical composition characterized in that at least one compound of formula (1) or a pharmaceutically acceptable salt or ester thereof is incorporated with a pharmaceutically acceptable carrier or diluent. 13. A process according to claim 1, characterized in that it proceeds substantially as described above in the Examples. - 14 * Process for the isolation and selection from natural sources of microorganisms capable of stereoselective oxidation of a compound of formula (II) in which R ^ represents an aryl group, optionally substituted, such as a phenyl or naphthyl group, or represents a heterocyclic ring system, which is optionally substituted, or represents a heteroaromatic ring system optionally containing in addition to the carbon atoms one or more nitrogen, sulfur or oxygen atoms, this ring system being optionally substituted and in which R ^ ® ^a S ^ru P ° alkyl containing at least 3 carbon atoms, to a compound of formula CH, R _x - CH (I) COOH with at least 7 CUo by weight .S configuration, characterized in that a natural source is contacted with a 2- (R ^) - alkane as a carbon source in a suitable medium. 15 * Process according to claim 16, characterized in that it represents a 6-methoxy-2-naphthyl group and the alkane is pentane, heptane or nonane. - 16¾ Process according to claim 1, characterized in that a microorganism chosen from the group Graphium fructicola (CBS 256.86), Exophiala mansonii (CBS 257.86), Exophiala mansonii (CBS 259.86) _t Exophiala jeanselmei var, .jeanselmei (CBS 258.86) and mutants or their derivative variants.